EP0178665A2 - Préparation stable d'érythropoiétine et procédé pour sa formulation - Google Patents

Préparation stable d'érythropoiétine et procédé pour sa formulation Download PDF

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Publication number
EP0178665A2
EP0178665A2 EP85113199A EP85113199A EP0178665A2 EP 0178665 A2 EP0178665 A2 EP 0178665A2 EP 85113199 A EP85113199 A EP 85113199A EP 85113199 A EP85113199 A EP 85113199A EP 0178665 A2 EP0178665 A2 EP 0178665A2
Authority
EP
European Patent Office
Prior art keywords
erythropoietin
stabilizer
sodium
preparation according
erythropoietin preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP85113199A
Other languages
German (de)
English (en)
Other versions
EP0178665A3 (fr
Inventor
Tsutomu Kawaguchi
Naoto Shimoda
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chugai Pharmaceutical Co Ltd
Original Assignee
Chugai Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chugai Pharmaceutical Co Ltd filed Critical Chugai Pharmaceutical Co Ltd
Publication of EP0178665A2 publication Critical patent/EP0178665A2/fr
Publication of EP0178665A3 publication Critical patent/EP0178665A3/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/22—Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention relates to a stable erythropoietin preparation and a process for formulating the same.
  • Erythropoietin is a circulating glycoprotein that stimulates the formation of red blood cells and is useful in the treatment or diagnosis of anemia.
  • a single dose of erythropoietin is as small as a few micrograms and this level must be strictly observed. In other words, erythropoietin must be administered in the acurately measured trace amount in which it is formulated in a dosage form.
  • an erythropoietin preparation contains one or more stabilizers selected from the group consisting of polyethylene glycol, protein, sugar, amino acid, inorganic salt, organic salt and sulfur-containing reducting agent.
  • a process for formulating a stable erythropoietin preparation containing one or more of the stabilizers listed above,
  • erythropoietin preparation in accordance with one aspect of the present invention is that at least one of the stabilizers listed above be mixed with erythropoietin.
  • This erythropoietin preparation may be formulated in any dosage form such as a liquid dosage form, a solid dosage form (e.g. tablet, capsule, fine granule, granule or powder), or semisolid dosage form (e.g. suppository).
  • the erythropoietin may be obtained by any known method; it may be extracted from human urine, followed by separation and purification; alternatively it may be produced in E. coli, yeasts or Chinese hamsters ovary cells by genetic engineering technology, and extracted from the culture by a variety of methods, followed by separation and purification.
  • the dosage of erythropoietin varies with the object of a specific diagnosis or treatment, and formulations containing 0.1 - 50 pg of erythropoietin per unit dosage form may be used. It should however be noted that the present invention is not limited by the erythropoietin content.
  • Proteins used as erythropoietin stabilizers include bovine serum albumin and gelatin; sugars include monosaccharides such as xylose, mannose, glucose and fructose, disaccharides such as lactose, maltose and sucrose, trisaccharides such as raffinose, polysaccharides such as dextran, sugar alcohols such as mannitol, sorbitol and glycerol, and cyclitols such as inositol; amino acids include glycine, alanine and lysine; inorganic salts include potassium chloride, calcium chloride, sodium phosphate, potassium phosphate and sodium hydrogencarbonate; organic salts include sodium citrate, potassium citrate and sodium acetate; and sulfur-containing reducing agents include glutathione, thioctic acid, sodium thioglycolate, thioglycerol, a-monothioglycerol and sodium thiosulf
  • These stabilizers are preferably incorporated in amounts of 0.1 - 10,000 parts by weight per part by weight of erythropoietin. Two or more of these stabilizers may be used if their total amount is within this range.
  • Erythropoietin may be administered by various .routes such as injection (e.g. iv or mv), oral administration into digestive tracts, and transmucous administration directed to the mucus of the rectum, oral cavity or nasal cavity.
  • Dosage forms suitable for the administration of erythropoietin include a liquid dosage form (e.g. injection), a solid dosage form (e.g. tablet, capsule, fine granule, granule or powder), and semisolid dosage form (e.g. suppository). Any conventional pharmaceutical additive may be mixed with erythropoietin as well as the stabilizers falling within the scope of the present invention so long as its stability is not impaired.
  • the stabilizer is used in the form of an aqueous solution having the proper concentration and pH.
  • the osmotic pressure ratio of this aqueous solution is generally in the range of 0.1 - 3.0, preferably 1.0.
  • the pH of the aqueous solution is generally adjusted to be within the range of 5.0 - 9.0, preferably 6.0 - 8.0.
  • An anti-adsorption agent is preferably used in formulating the erythropoietin preparation of the present invention in the form of a solution such as injection, or when handling erythropoietin in the liquid state during formulation.
  • Erythropoietin derived from human urine (0.1 mg) was dissolved in 200 ml of 0.01% lecithin suspension and 5-ml portions of the solution were charged into test tubes.
  • the stabilizers shown in the following table were put into the test tubes in the amounts also indicated in the table.
  • Each of the mixtures was distributed among 10 vials in amounts of 0.5 ml and freeze-dried. The 10 vials were divided into two groups, each consisting of 5 vials.
  • the freeze-dried mixtures of one group were immediately dissolved in an aqueous solution containing 0.1% bovine serum albumin, 0.15M NaCl and 0.01M CaCl 2 , and the mixtures of the other group were left to stand at 37°C for one month before they were dissolved in the same solution.
  • the activity of erythropoietin in each group was measured by the fasted rat method described in Goldwasser, E. & Gross, M., Methods in Enzymol., vol. 37, pp. 109 - 121 (1975).
  • the percentage of residual activity was determined, with the value for the first group (dissolved in aqueous solution immediately after freeze- drying) being taken as 100.
  • the results are shown in the following table in the column of "Percentage of residual activity - Freeze-dried". Each of the figures in the column was a mean of five measurements. The data in the table show the effectiveness of the stabilizing agents specified by the present invention.
  • the percentage of residual activity was determined, with the average value for the first group being taken as 100.
  • the results are shown in the following table in the column of "Percentage of residual activity - Aqueous solution".
  • the data show that the stabilizers in accordance with the present invention are also effective in stabilizing the activity of erythropoietin in an aqueous solution.
  • An aqueous solution having the above composition was aseptically prepared, distributed among vials and freeze-dried, followed by the hermetic sealing of the vials.
  • a freeze-dried erythropoietin preparation was formulated as in Example 1 except that 100 parts by weight of gelatin was replaced by an equal amount of dextran 40.
  • a freeze-dried erythropoietin preparation was formulated as in Example 1 except that 100 parts by weight of gelatin was replaced by 500 parts by weight of polyethylene glycol 4 000.
  • An aqueous solution having the above composition was aseptically prepared, distributed among vials and freeze-dried, followed by the hermetic sealing of the vials.
  • a freeze-dried erythropoietin preparation was formulated as in Example 4 except that the glycine and mannitol were replaced by 200 parts by weight of gelatin and 500 parts by weight of CaC1 2 .
  • An aqueous solution having the above composition was aseptically prepared, distributed among vials and freeze-dried, followed by the hermetic sealing of the vials.
  • a freeze-dried erythropoietin preparation was formulated as in Example 6 except that the glutathione and glucose were replaced by 10 parts by weight of thioglycerol and 500 parts by weight of maltose.
  • An aqueous solution having the above composition was aseptically prepared and distributed among ampules which were then sealed by fusing.
  • An ampule solution was prepared as in Example 8 except that the disodium hydrogenphosphate, potassium dihydrogenphosphate and NaCl were replaced by 98 parts by weight of sodium dihydrogenphosphate.2H 2 0, 12 parts by weight of citric acid monohydrate and 500 parts by weight of sucrose.
  • a mixture of mannitol (5,000 parts by weight), erythropoietin (1 part by weight), human serum albumin (100 parts by weight), sodium acetyltryptophanate (2.154 parts by weight) and sodium caprylate (1.33 parts by weight) was dissolved in purified water to make a total of 10 5 parts by weight, and the resulting aqueous solution was freeze-dried.
  • the freeze-dried product was charged into capsules specified in the Japanese Pharmacopoeia, which were covered with an enteric coating agent by a known method, so as to make enteric capsules.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Inorganic Chemistry (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
EP85113199A 1984-10-18 1985-10-17 Préparation stable d'érythropoiétine et procédé pour sa formulation Withdrawn EP0178665A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP59219000A JPS6197229A (ja) 1984-10-18 1984-10-18 安定なエリトロポエチン製剤
JP219000/84 1984-10-18

Publications (2)

Publication Number Publication Date
EP0178665A2 true EP0178665A2 (fr) 1986-04-23
EP0178665A3 EP0178665A3 (fr) 1989-02-08

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ID=16728693

Family Applications (1)

Application Number Title Priority Date Filing Date
EP85113199A Withdrawn EP0178665A3 (fr) 1984-10-18 1985-10-17 Préparation stable d'érythropoiétine et procédé pour sa formulation

Country Status (5)

Country Link
US (1) US4806524A (fr)
EP (1) EP0178665A3 (fr)
JP (1) JPS6197229A (fr)
KR (1) KR860003019A (fr)
CA (1) CA1258629A (fr)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2190838A (en) * 1986-05-27 1987-12-02 Sandoz Ltd Pharmaceutical compositions containing polypeptides
EP0252759A2 (fr) * 1986-07-10 1988-01-13 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Procédé pour préparer des produits solides comprenant une substance liposoluble
EP0252760A2 (fr) * 1986-07-10 1988-01-13 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Procédé pour préparer des produits solides comprenant une substance liposoluble
EP0274812A2 (fr) * 1986-12-29 1988-07-20 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Emulsifiant composite pulvérulent, préparation et utilisation
GB2207050A (en) * 1987-06-19 1989-01-25 Hunchplan Limited Parenteral drug delivery composition
EP0306824A2 (fr) * 1987-09-05 1989-03-15 Roche Diagnostics GmbH Préparations de protéines humaines stabilisées
WO1991011200A1 (fr) * 1990-01-29 1991-08-08 Janssen Pharmaceutica N.V. Composition d'erythropoïetine amelioree a base de cyclodextrine
EP0456153A1 (fr) * 1990-05-08 1991-11-13 BEHRINGWERKE Aktiengesellschaft Formulations galéniques aqueuses à base d'érythropoiétine et leur utilisation
EP0459795A1 (fr) * 1990-06-01 1991-12-04 Kirin-Amgen, Inc. Formes d'administration orale de protéines biologiquement actives
EP0459516A1 (fr) * 1990-06-01 1991-12-04 Kirin-Amgen, Inc. Formes d'administration orale de protéines biologiquement actifs
US5130418A (en) * 1989-05-02 1992-07-14 California Biotechnology Inc. Method to stabilize basic fibroblast growth factor
EP0528314A1 (fr) * 1991-08-15 1993-02-24 Roche Diagnostics GmbH Procédé de préparation de médicaments tolérables à base de protéine humaine pour perfusion au injection
EP0595716A1 (fr) * 1992-10-29 1994-05-04 Kureha Chemical Industry Co., Ltd. Agent améliorant l'effet antianémique d'érythropoiètine
WO1996002239A2 (fr) * 1994-07-18 1996-02-01 University Of Cincinnati Amelioration du chargement de solutes dans des gels polymeres et procedes d'utilisation
WO1996018647A1 (fr) * 1994-12-16 1996-06-20 Ortho Pharmaceutical Corporation Erythropoietine sechee par pulverisation
EP0841066A1 (fr) * 1995-06-08 1998-05-13 Kirin Brewery Company, Ltd. Composition lyophilisee stable contenant de la thrombopoietine (tpo)
US5840338A (en) * 1994-07-18 1998-11-24 Roos; Eric J. Loading of biologically active solutes into polymer gels
WO2001087329A1 (fr) * 2000-05-15 2001-11-22 F. Hoffmann-La Roche Ag Nouvelle composition pharmaceutique
WO2002011753A1 (fr) * 2000-08-04 2002-02-14 Chugai Seiyaku Kabushiki Kaisha Preparations proteiniques a injecter
WO2004019966A1 (fr) * 2002-08-27 2004-03-11 Chugai Seiyaku Kabushiki Kaisha Methode de stabilisation de preparations de solution de proteines
WO2005087804A1 (fr) * 2004-03-10 2005-09-22 Bioceuticals Arzneimittel Ag Formulation liquide d'erythropoietine
EP0909564B1 (fr) * 1996-04-26 2006-06-21 Chugai Seiyaku Kabushiki Kaisha Solution d'erythropoietine stabilisee par des acides amines
US7662854B2 (en) 2002-03-21 2010-02-16 Isis Innovation Limited HIF hydroxylase inhibitors
WO2014164301A2 (fr) * 2013-03-11 2014-10-09 Amgen Inc. Formulations protéiques
US9375470B2 (en) 2008-11-28 2016-06-28 Circassia Limited Compositions with reduced dimer formation

Families Citing this family (60)

* Cited by examiner, † Cited by third party
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KR850004274A (ko) * 1983-12-13 1985-07-11 원본미기재 에리트로포이에틴의 제조방법
GB2177914B (en) * 1985-06-04 1989-10-25 Chugai Pharmaceutical Co Ltd A pharmaceutical composition containing human erythropoietin and a surface active agent for nasal administration for the treatment of anemia
US5237054A (en) * 1987-02-20 1993-08-17 Akzo Pharma Stabilized aqueous composition containing antibodies
JPS63227527A (ja) * 1987-03-05 1988-09-21 キリン―アムジエン（デラウエア）インコーポレーテツド 貧血予防薬
CA1336401C (fr) * 1987-10-15 1995-07-25 Brian H. Vickery Administration intranasale de polypeptides sous forme de poudre
CA1322957C (fr) * 1988-03-30 1993-10-12 Hitoshi Yamauchi Onguents a base de derives d'amp cyclique
DE3900649A1 (de) * 1989-01-11 1990-07-12 Boehringer Mannheim Gmbh Verfahren zur abloesung eines analyten von seinem bindeprotein
DE3939346A1 (de) * 1989-11-29 1991-06-06 Behringwerke Ag Arzneimitel zur subkutanen oder intramuskulaeren applikation enthaltend polypeptide
US5384132A (en) * 1990-03-20 1995-01-24 Akzo N.V. Stabilized gonadotropin containing preparations
US5270057A (en) * 1990-03-20 1993-12-14 Akzo N.V. Stabilized gonadotropin containing preparations
JPH078804B2 (ja) * 1990-08-28 1995-02-01 三菱化学株式会社 副腎皮質刺激ホルモン放出因子含有製剤
US5290764A (en) * 1992-01-14 1994-03-01 The Dupont Merck Pharmaceutical Company Stabilization of active plasminogen activator inhibitor-1
FR2686899B1 (fr) 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant.
US5912015A (en) 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
US5716644A (en) * 1992-06-11 1998-02-10 Alkermes, Inc. Composition for sustained release of non-aggregated erythropoietin
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DK0644771T4 (da) † 1992-06-11 2006-12-27 Alkermes Inc Lægemiddelsystem til levering af erythropoietin
US5661125A (en) * 1992-08-06 1997-08-26 Amgen, Inc. Stable and preserved erythropoietin compositions
US5358708A (en) * 1993-01-29 1994-10-25 Schering Corporation Stabilization of protein formulations
US5656730A (en) * 1995-04-07 1997-08-12 Enzon, Inc. Stabilized monomeric protein compositions
EP0850051A2 (fr) * 1995-08-31 1998-07-01 Alkermes Controlled Therapeutics, Inc. Composition se pretant a la liberation prolongee d'un agent
DE19539574A1 (de) * 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Zubereitungen und Verfahren zur Stabilisierung biologischer Materialien mittels Trocknungsverfahren ohne Einfrieren
US6072040A (en) * 1996-10-15 2000-06-06 Medical Analysis Systems, Inc. Stabilized conjugates of uncomplexed subunits of multimeric proteins
PT986644E (pt) * 1997-07-23 2007-01-31 Roche Diagnostics Gmbh Preparação de eritropoietina por activação genética endógena com promotores virais
US6548296B1 (en) * 1997-07-23 2003-04-15 Roche Diagnostics Gmbh Methods for identifying human cell lines useful for endogenous gene activation, isolated human lines identified thereby, and uses thereof
ATE271376T1 (de) * 1998-02-23 2004-08-15 Cilag Ag Int Liposomale erythropoietin-dispersion
AU2945199A (en) * 1998-03-18 1999-10-11 Ronai, Peter Amorphous glasses for stabilising sensitive products
US7304150B1 (en) * 1998-10-23 2007-12-04 Amgen Inc. Methods and compositions for the prevention and treatment of anemia
US6777205B1 (en) 1998-11-06 2004-08-17 Sterrenbeld Biotechnologie North America, Inc. Host cells expressing recombinant human erythropoietin
BR9917606A (pt) 1998-11-06 2002-12-31 Bio Sidus S A Procedimento para a purificação de eritropoetina humana recombinante a partir de sobrenadantes de cultivo de células e eritropoetina humana recombinante obtida com tal procedimento
BR9905868A (pt) 1998-11-06 2001-01-23 Bio Sidus S A Procedimento de cultivo massivo de células de mamìfero para a obtenção de eritropoetina humana, recombinante e a eritropoetina humana recombinante obtida com tal procedimento
UY25790A1 (es) * 1998-11-06 2000-08-21 Bio Sidus S A Formas farmaceuticas de eritropoyetina humana recombinante estables a temperatura ambiente y apropiadas para su uso en humanos, formulaciones y procedimientos de liofilizacion para su obtencion.
DE19857609A1 (de) 1998-12-14 2000-06-15 Hannelore Ehrenreich Verwendung von Erythropoietin zur Behandlung von cerebralen Ischämien des Menschen
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EP0178665A3 (fr) 1989-02-08
JPS6197229A (ja) 1986-05-15
US4806524A (en) 1989-02-21
CA1258629A (fr) 1989-08-22
KR860003019A (ko) 1986-05-19

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